Enzymes and hormones are biocatalysts which control the metabolic processes of an organism. As catalysts, enzymes and hormones increase the rate of one or more reactions and function as directive agents for these occurring reactions. They are of essential importance for living cells. In the blood circulation, enzymes are only present in very limited amounts. They are stored in specific cells in an inactive, insoluble form, and are activated in accordance with the metabolic needs of the organism. The inactive form of the stored enzymes, referred to as zymogens, are enzyme precursors. The activation reaction may be schematically represented as follows: EQU INACTIVE ZYMOGEN.fwdarw.ENZYME+INHIBITOR+CLEAVED PEPTIDES.
The best known example for the activation process is the pepsinogen compound which is converted into pepsin. In the same way prorenin is activated into renin, and proinsulin into insulin. The reversal of the activation process of zymogen is the blocking of the active enzyme by an inhibitor. A typical example of this process is the pepsinogen-pepsin relationship where pepsin is produced by the activation of pepsinogen. The inhibition of pepsin by an inhibitor produces an inactive compound. Other examples with the possible reversibility of the reaction are the enzymes cathepsin, renin, papain and others.
The principle of the inhibition of an enzymatic reaction is based upon the ability of many organic compounds to react with the enzyme protein, either reversibly or irreversibly, and thus, preventing a reaction between the enzyme and the substrate. It follows that the cleaved inhibitor produced during the activation of the zymogen when reunited with the active enzyme should result in the original zymogen.
Examples of previous studies relating to the structure of pepsin and pepsinogen as well as pepsin are disclosed in Vunakis et al., "Structural Changes Associated with the Conversion of Pepsinogen to Pepsin", Biochemica Et Biophysica ACTA, Vol. 22, pp. 537-43 (1956) and Vunakis et al., "Structural Changes Associated with the Conversion of Pepsinogen to Pepsin", Biochemica Et Biophysica ACTA, Vol. 23, pp. 600-5 (1957) which are hereby incorporated by reference.
Numerous chemical compounds have been proposed for blocking the renin angiotensin enzymatic process and thereby controlling or treating hypertension. Examples of related processes are disclosed in U.S. Pat. Nos. 5,008,273 to Schnorrenberg et al.; 4,478,827 to Haber et al.; and 5,134,123 to Branca et al.; which are hereby incorporated by reference.
These processes have met with limited success. Accordingly, there is a continuing need in the art for inhibitor compounds, especially of body own-endogenous origin, controlling the blood pressure mechanism.